Gender-specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states.

BACKGROUND AND AIMS: Depression and anxiety are often comorbid with alcoholism and contribute to craving and relapse. We aimed to estimate the prevalence of life-time diagnoses of major depressive disorder (MDD), substance-induced depression (SID), anxiety disorder (AnxD) and substance-induced anxiety (SIA), the effects of these comorbidities on the propensity to drink in negative emotional states (negative craving), and test whether these effects differ by sex. DESIGN: Secondary analyses of baseline data collected in a single-arm study of pharmacogenetic predictors of acamprosate response. SETTING: Academic medical center and affiliated community-based treatment programs in the American upper mid-west. PARTICIPANTS: A total of 287 males and 156 females aged 18-80 years, meeting DSM-IV criteria for alcohol dependence. MEASUREMENTS: The primary outcome measure was 'propensity to drink in negative emotional situations' (determined by the Inventory of Drug Taking Situations) and the key predictors/covariates were sex and psychiatric comorbidities, including MDD, SID, AnxD and SIA (determined by Psychiatric Research Interview of Substance and Mood Disorders). FINDINGS: The prevalence of the MDD, SID and AnxD was higher in females compared with males (33.1 versus 18.4%, 44.8 versus 26.4% and 42.2 versus 27.4%, respectively; P < 0.01, each), while SIA was rare (3.3%) and did not differ by sex. Increased propensity to drink in negative emotional situations was associated with comorbid MDD (ß = 6.6, P = 0.013) and AnxD (ß = 4.8, P = 0.042) as well as a SID × sex interaction effect (P = 0.003), indicating that the association of SID with propensity to drink in negative emotional situations differs by sex and is stronger in males (ß = 7.9, P = 0.009) compared with females (ß = -6.6, P = 0.091). CONCLUSIONS: There appears to be a higher prevalence of comorbid depression and anxiety disorders as well as propensity to drink in negative emotional situations in female compared with male alcoholics. Substance-induced depression appears to have a sex-specific effect on the increased risk for drinking in negative emotional situations in males.

A review of the clinical, economic, and societal burden of treatment-resistant depression: 1996-2013.

OBJECTIVE: This literature review assessed the burden of treatment-resistant depression in the United States by compiling published data about the clinical, societal, and economic outcomes associated with failure to respond to one or more adequate trials of drug therapy. METHODS: PubMed and the Tufts Cost-Effectiveness Analyses Registry were searched for English-language articles published between January 1996 and August 2013 that collected primary data about treatment-resistant depression. Two researchers independently assessed study quality and extracted data. RESULTS: Sixty-two articles were included (N=59,462 patients). Patients with treatment-resistant depression had 3.8±2.1 prior depressive episodes and illness duration of 4.4±3.3 years and had completed 4.7±2.7 unsuccessful drug trials involving 2.1±.3 drug classes. Response rates for treatment-resistant depression were 36%±1%. A total of 17%±6% of patients had prior suicide attempts (1.1±.2 attempts per patient). Quality-of-life scores (scale of 0-1, with 0 indicating death and 1 indicating perfect health) for patients with treatment-resistant depression were .41±.8 and .26±.8 points lower, respectively, than for patients who experienced remission or response. Annual costs for health care and lost productivity were $5,481 and $4,048 higher, respectively, for patients with treatment-resistant versus treatment-responsive depression. CONCLUSIONS: Treatment-resistant depression exacts a substantial toll on patients' quality of life. At current rates of 12%-20% among all depressed patients, treatment-resistant depression may present an annual added societal cost of $29-$48 billion, pushing up the total societal costs of major depression by as much as $106-$118 billion. These findings underscore the need for research on the mechanisms of depression, new therapeutic targets, existing and new treatment combinations, and tests to improve the efficacy of and adherence to treatments for treatment-resistant depression.

Treatment outcomes of depression: the pharmacogenomic research network antidepressant medication pharmacogenomic study.

BACKGROUND: The effectiveness of selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder (MDD) is controversial. AIMS: The clinical outcomes of subjects with nonpsychotic MDD were reported and compared with the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study outcomes to provide guidance on the effectiveness of SSRIs. METHODS: Subjects were treated with citalopram/escitalopram for up to 8 weeks. Depression was measured using the Quick Inventory of Depressive Symptomatology-Clinician Rated (QIDS-C16) and the 17-item Hamilton Depression Rating Scale. RESULTS: The group of subjects with at least 1 follow-up visit had a remission (QIDS-C16 ≤ 5) rate of 45.8% as well as a response (50% reduction in QIDS-C16) rate of 64.8%, and 79.9% achieved an improvement of 5 points or higher in QIDS-C16 score. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study subjects were more likely to achieve a response than STAR*D study subjects. After adjustment for demographic factors, the response rates were not significantly different. When reporting the adverse effect burden, 60.5% of the subjects reported no impairment, 31.7% reported a minimal-to-mild impairment, and 7.8% reported a moderate-to-severe burden at the 4-week visit. CONCLUSIONS: Patients contemplating initiating an SSRI to treat their MDD can anticipate a high probability of symptom improvement (79.9%) with a low probability that their symptoms will become worse. Patients with lower baseline severity have a higher probability of achieving remission. The Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study replicates many findings of the first phase of the STAR*D study after controlling for the differences between the studies.

Citalopram and escitalopram plasma drug and metabolite concentrations: genome-wide associations.

AIMS: Citalopram (CT) and escitalopram (S-CT) are among the most widely prescribed selective serotonin reuptake inhibitors used to treat major depressive disorder (MDD). We applied a genome-wide association study to identify genetic factors that contribute to variation in plasma concentrations of CT or S-CT and their metabolites in MDD patients treated with CT or S-CT. METHODS: Our genome-wide association study was performed using samples from 435 MDD patients. Linear mixed models were used to account for within-subject correlations of longitudinal measures of plasma drug/metabolite concentrations (4 and 8 weeks after the initiation of drug therapy), and single-nucleotide polymorphisms (SNPs) were modelled as additive allelic effects. RESULTS: Genome-wide significant associations were observed for S-CT concentration with SNPs in or near the CYP2C19 gene on chromosome 10 (rs1074145, P = 4.1 × 10(-9) ) and with S-didesmethylcitalopram concentration for SNPs near the CYP2D6 locus on chromosome 22 (rs1065852, P = 2.0 × 10(-16) ), supporting the important role of these cytochrome P450 (CYP) enzymes in biotransformation of citalopram. After adjustment for the effect of CYP2C19 functional alleles, the analyses also identified novel loci that will require future replication and functional validation. CONCLUSIONS: In vitro and in vivo studies have suggested that the biotransformation of CT to monodesmethylcitalopram and didesmethylcitalopram is mediated by CYP isozymes. The results of our genome-wide association study performed in MDD patients treated with CT or S-CT have confirmed those observations but also identified novel genomic loci that might play a role in variation in plasma levels of CT or its metabolites during the treatment of MDD patients with these selective serotonin reuptake inhibitors.

Association of GATA4 sequence variation with alcohol dependence.

To further explore reports of association of alcohol dependence and response to acamprosate treatment with the GATA4 rs13273672 single nucleotide polymorphism (SNP), we genotyped this and 10 other GATA4 SNPs in 816 alcohol-dependent cases and 1248 controls. We tested for association of alcohol dependence with the 11 SNPs individually and performed a global test for association using a principle components analysis. Our analyses demonstrate significant association between GATA4 and alcohol dependence at the gene level (P = 0.009) but no association with rs13273672. Further studies are needed to identify potential causal GATA4 variation(s) and the functional mechanism(s) contributing to this association.

Does 5HTTLPR long allele prevent hospitalization? Test of Hardy-Weinberg equilibrium.

Many studies suggest an association of the serotonin transporter gene polymorphism (5HTTLPR) long allele with better antidepressant treatment response than the short allele. However, there is controversy over these findings. We hypothesized that if the long allele is associated with a better outcome, we would find fewer inpatients with the long allele compared with the short allele. Chart review identified 925 depressed inpatients and 201 outpatients genotyped for 5HTTLPR. The sample was primarily White (>90%). We tested potential departures from Hardy-Weinberg equilibrium for each sample. We analyzed three independent sets of inpatient samples separately and combined, a White subgroup of 791 patients of the total 925 inpatients, and 201 outpatients. There was no departure from Hardy-Weinberg equilibrium with any of these samples. We also compared 5HTTLPR genotype prevalence between 925 inpatients and 201 outpatients, which showed no statistically significant difference.

SLC6A4 polymorphisms and age of onset in late-life depression on treatment outcomes with citalopram: a Sequenced Treatment Alternatives to Relieve Depression (STAR*D) report.

OBJECTIVE: Age at onset of first major depressive episode (MDE) does not necessarily translate into different treatment outcomes to antidepressants in late-life depression. The influence of genetic variants may affect this relationship. DESIGN: Post hoc data set analysis of the association between variants in the promoter region (indel, rs25531) and within intron 2 (Stin2 VNTR) of the SCL6A4 gene and treatment outcomes among older participants in the first treatment arm of the Sequenced Treatment Alternatives to Relieve Depression trial (STAR*D). SETTING: Participants were enrolled from 23 psychiatric and 18 primary care settings. PARTICIPANTS: Two hundred twenty-one, white non-Hispanic subjects, aged 60 to 75 years, with 16-item Quick Inventory of Depressive Symptomatology-Clinician Rating (QIDS-CR16) initial score ≥10, and who remained in the study for at least 6 weeks, were genotyped. INTERVENTION: Citalopram treatment for up to 14 weeks. MEASUREMENTS: Main outcome was remission rate defined as a score of ≤5 on the QIDS-CR16. Response was a secondary outcome defined as a reduction of ≥50% of baseline QIDS-CR16. RESULTS: Polymorphism in the indel promoter region was associated with remission among subjects whose first lifetime episode of major depression occurred later than age 55. In this group, subjects with L/L genotype had significantly higher remission (80% versus 43%) compared to those subjects with any other indel promoter genotype. Multivariate analysis demonstrated that the genetic effect of the indel promoter region on remission increases along with age at onset of MDE. CONCLUSIONS: Variants in the indel promoter region of the SLC6A4 gene have a more robust effect to antidepressant outcome among older subjects who experienced their first MDE at a later age. The mechanism of action of these variants remains to be determined.

Utility of integrated pharmacogenomic testing to support the treatment of major depressive disorder in a psychiatric outpatient setting.

OBJECTIVE: The objective was to evaluate the potential benefit of an integrated, five-gene pharmacogenomic test and interpretive report (GeneSight) for the management of psychotropic medications used to treat major depression in an outpatient psychiatric practice. METHODS: The open-label study was divided into two groups. In the first (unguided) group (n = 113), pharmacogenomic information was not shared until all participants completed the study. In the second (guided) group (n = 114), the pharmacogenomic report was provided to physicians for clinical use. Three depression ratings, the 17-item Hamilton Rating Scale for Depression (HAMD-17), the Quick Inventory of Depressive Symptomatology - Clinician Rated (QIDS-C16), and the Patient Health Questionnaire (PHQ-9), were collected at baseline, and at 2, 4, and 8 weeks. RESULTS: The guided group experienced greater percent improvement in depression scores from baseline on all three depression instruments (HAMD-17, P < 0.0001; QIDS-C16, P < 0.0001; PHQ-9, P < 0.0001) compared with the unguided group. Eight-week response rates were higher in the guided group than in the unguided group on all three measurements (HAMD-17, P = 0.03; QIDS-C16, P = 0.005; PHQ-9, P = 0.01). Eight-week QIDS-C16 remission rates were higher in the guided group (P = 0.03). Participants in the unguided group who at baseline were prescribed a medication that was most discordant with their genotype experienced the least improvement compared with other unguided participants (HAMD-17, P = 0.007). Participants in the guided group and on a baseline medication most discordant with their genotype showed the greatest improvement compared with the unguided cohort participants (HAMD-17, P = 0.01). CONCLUSION: These findings replicate previous studies and demonstrate significantly improved depression outcomes with use of GeneSight, an integrated, multigenetic pharmacogenomic testing platform.

A retrospective study of gender differences in depressive symptoms and risk of relapse in patients with alcohol dependence.

BACKGROUND AND OBJECTIVES: The aim of this study was to investigate potential gender differences in situations associated with heavy alcohol drinking. METHODS: Data from 395 alcohol dependent patients participating in the Mayo Clinic Intensive Addiction Program were evaluated. Each participant completed the inventory of drug taking situations (IDTS), Penn alcohol craving scale (PACS), patient health questionnaire (PHQ-9), and/or Beck depression inventory (BDI). Gender differences in IDTS scores representing three domains (negative, positive, and temptation) of situations associated with heavy alcohol use were examined. RESULTS: Women with alcohol dependence report a higher frequency of heavy drinking in unpleasant emotional (IDTS negative scores mean ± SD women vs. men: 52.3 ± 22.1 vs. 43.8 ± 21.8; p = .0006), and as a result of temptation (IDTS temptation scores mean ± SD women vs. men: 40.4 ± 23.0 vs. 35.3 ± 20.8; p = .035). Upon admission, women also scored significantly higher on depressive symptoms as measured by the BDI (23.4 ± 11.4 vs. 18.2 ± 9.8, p < .001). After controlling for depressive symptom severity as a covariate, the IDTS gender differences were no longer significant. CONCLUSION AND SCIENTIFIC SIGNIFICANCE: Our results suggest that unpleasant or temptation based emotional situations are a vulnerability risk factor for heavy drinking particularly in females. This risk appears to be at least partially driven by depressive symptom burden. Future research is needed to further investigate this finding.

"Diminished" association between the serotonin transporter linked polymorphism (5HTTLPR) and body mass index in a large psychiatric sample.

BACKGROUND: The role of the promoter polymorphism (5HTTLPR) of the serotonin transporter gene (SLC6A4) in psychiatric illnesses has been studied extensively. Serotonergic function also regulates many central nervous system, including appetite and feeding behaviors. The 5HTTLPR short allele was found to be associated with increased body mass index and obesity risk among the general population. No data is available to support generalizability of such association among psychiatric population. METHODS: We examined the relationship between BMI and the 5HTTLPR genotype in a large sample of 1831 psychiatric patients at Mayo Clinic, Rochester, Minnesota, using a retrospective chart review. RESULTS: Average BMI among groups with the short/short (28.29 ± 7.27 kg/m(2)), the short/long (28.07 ± 6.45 kg/m(2)) and the long/long (28.15 ± 7.51 kg/m(2)) genotypes of 5HTTLPR were not statistically different. This negative association persisted even with the sub-analysis of the Caucasians. However, we observed an increased rate of obesity among our psychiatric patient sample compared to the general population of Minnesota (36.6% versus 27.6%, p=0.0001 for males, 30.3% versus 24.4%, p=0.0001 for females). Also, sub-analysis showed female inpatients to have a significantly higher average BMI than outpatients (28.64 ± 8.08 kg/m(2) versus 27.13 ± 6.92 kg/m(2), p=0.026). This confirmed a significant association between mental health disorder and BMI. LIMITATIONS: Retrospective study design with limited control for potential confounders. CONCLUSIONS: In this large sample of psychiatric patients we found no significant association between 5HTTLPR genotype and BMI, which is different from the case with general population reported in the literature.

HTR2A gene-child abuse interaction and association with a history of suicide attempt among Caucasian depressed psychiatric inpatients.

BACKGROUND: The serotonin transporter gene polymorphism (5HTTLPR) has been associated with vulnerability for depression after exposure to stressful life event as well as with difference in treatment response to SSRI. Although the A/A genotype of the serotonin receptor SNP (rs7997012) was associated with better citalopram response than the G/G in the STAR⁎D sample, the effects of this SNP in the moderation of child abuse history on the characteristics of mental illnesses are not well understood. We examined if there are similar gene-environment interaction with the SNP. METHODS: Retrospective chart review of 250 Caucasian depressed psychiatric inpatients, who had genotype for rs7997012. Subjects with each genotype were subcategorized into 2 groups with/without history of child abuse. The history of suicide attempts of each group was compared. RESULTS: A trend for an interaction was found between the HTR2A genotype and child abuse history influencing the prevalence of suicide attempts. Although each genotype did not show significant difference in the risk of suicide attempt when there was no abuse history, the A carriers (A/A+A/G) showed significantly higher rate of suicide attempt compared to the G/G when there is a history of child abuse (48.4% versus 22.7% respectively, p=0.0050). The likelihood ratio test from the logistic model showed a trend for an interaction between the A/A genotype and abuse history (Odds Ratio 2.10, χ(2)=2.49, p=0.11). LIMITATIONS: Retrospective study design and small sample size with borderline significance. CONCLUSIONS: Our findings showed a potential interaction between the HTR2A gene and stressful life events.

Replication of genome wide association studies of alcohol dependence: support for association with variation in ADH1C.

Genome-wide association studies (GWAS) have revealed many single nucleotide polymorphisms (SNPs) associated with complex traits. Although these studies frequently fail to identify statistically significant associations, the top association signals from GWAS may be enriched for true associations. We therefore investigated the association of alcohol dependence with 43 SNPs selected from association signals in the first two published GWAS of alcoholism. Our analysis of 808 alcohol-dependent cases and 1,248 controls provided evidence of association of alcohol dependence with SNP rs1614972 in the ADH1C gene (unadjusted p = 0.0017). Because the GWAS study that originally reported association of alcohol dependence with this SNP [1] included only men, we also performed analyses in sex-specific strata. The results suggest that this SNP has a similar effect in both sexes (men: OR (95%CI) = 0.80 (0.66, 0.95); women: OR (95%CI) = 0.83 (0.66, 1.03)). We also observed marginal evidence of association of the rs1614972 minor allele with lower alcohol consumption in the non-alcoholic controls (p = 0.081), and independently in the alcohol-dependent cases (p = 0.046). Despite a number of potential differences between the samples investigated by the prior GWAS and the current study, data presented here provide additional support for the association of SNP rs1614972 in ADH1C with alcohol dependence and extend this finding by demonstrating association with consumption levels in both non-alcoholic and alcohol-dependent populations. Further studies should investigate the association of other polymorphisms in this gene with alcohol dependence and related alcohol-use phenotypes.

FKBP5 genetic variation: association with selective serotonin reuptake inhibitor treatment outcomes in major depressive disorder.

OBJECTIVES: FKBP51 (51 kDa immunophilin) acts as a modulator of the glucocorticoid receptor and a negative regulator of the Akt pathway. Genetic variation in FKBP5 plays a role in antidepressant response. The aim of this study was to comprehensively assess the role of genetic variation in FKBP5, identified by both Sanger and Next Generation DNA resequencing, as well as genome-wide single nucleotide polymorphisms (SNPs) associated with FKBP5 expression in the response to the selective serotonin reuptake inhibitor (SSRI) treatment of major depressive disorder. METHODS: We identified 657 SNPs in FKBP5 by Next Generation sequencing of 96 DNA samples from white patients, and 149 SNPs were selected for the genotyping together with 235 SNPs that were trans-associated with variation in FKBP5 expression in lymphoblastoid cells. A total of 529 DNA samples from the Mayo Clinic PGRN-SSRI Pharmacogenomic trial for which genome-wide SNPs had already been obtained were genotyped for these 384 SNPs, and associations with treatment outcomes were determined. The most significant SNPs were genotyped using 96 DNA samples from white non-Hispanic patients of the NIMH-supported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study to attempt replication, followed by functional genomic studies. RESULTS: Genotype-phenotype association analysis indicated that rs352428 was associated with both 8-week treatment response in the Mayo study (odds ratio=0.49; P=0.003) and 6-week response in the STAR*D replication study (odds ratio=0.74; P=0.05). The electrophoresis mobility shift assay and the reporter gene assay confirmed the possible role of this SNP in transcription regulation. CONCLUSION: This comprehensive FKBP5 sequence study provides insight into the role of common genetic polymorphisms that might influence SSRI treatment outcomes in major depressive disorder patients.

Prospectively assessed early life experiences in relation to cortisol reactivity in adolescents at risk for asthma.

Altered cortisol reactivity in individuals with asthma likely increases the risk of inflammation in the face of stress. Understanding antecedents of cortisol reactivity enhances knowledge of factors affecting asthma. Forty-eight subjects genetically predisposed for asthma, recruited from a study that assessed them from birth, completed a laboratory stress procedure and self-report measures at ages 17-19 years. Observation and parent reports from age 0 to 2 years were used to create a parent child relationship risk variable and to define criteria for a cumulative risk variable. In repeated measures analysis of 46 adolescents, those who had experienced early parent child relationship problems, specifically insecure attachment, had an attenuated cortisol stress response, even after controlling for concurrent psychological function and recent stressors (F = 4.6, p < .005). Cortisol stress response was not related to asthma status. This study supports a relationship between the parent child relationship during the first 2 years of life and later cortisol response to stress in youth at genetic risk for asthma.

Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states.

Synthetic κ-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol-dependent subjects and investigated their association with: (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations; (2) a self-reported history of depression; (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II. In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p = 0.00079) and with negative craving (p = 0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p = 0.024) and alcohol dependence (p = 0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol-dependent subjects.

Ethanol withdrawal-induced brain metabolites and the pharmacological effects of acamprosate in mice lacking ENT1.

Acamprosate is clinically used to treat alcohol-dependent patients. While the molecular and pharmacological mechanisms of acamprosate remain unclear, it has been shown to regulate γ-aminobutyric acid (GABA) or glutamate levels in the cortex and striatum. To investigate the effect of acamprosate on brain metabolites in the medial prefrontal cortex (mPFC) and nucleus accumbens (NAc), we employed in vivo 16.4 T proton magnetic resonance spectroscopy. We utilized type 1 equilibrative nucleoside transporter (ENT1) null mice since acamprosate attenuates ethanol drinking in these mice. Our findings demonstrated that ethanol withdrawal reduced GABA levels and increased phosphorylated choline compounds in the mPFC of both wild-type and ENT1 null mice. Notably, acamprosate normalized these withdrawal-induced changes only in ENT1 null mice. In the NAc, ethanol withdrawal increased glutamate and glutamine (Glx) levels only in wild-type mice. Interestingly, acamprosate reduced Glx levels in the NAc compared to the withdrawal state in both genotypes. These results provide a molecular basis for the pharmacological effect of acamprosate in the cortical-striatal circuit.

Merging pharmacometabolomics with pharmacogenomics using '1000 Genomes' single-nucleotide polymorphism imputation: selective serotonin reuptake inhibitor response pharmacogenomics.

OBJECTIVE: We set out to test the hypothesis that pharmacometabolomic data could be efficiently merged with pharmacogenomic data by single-nucleotide polymorphism (SNP) imputation of metabolomic-derived pathway data on a 'scaffolding' of genome-wide association (GWAS) SNP data to broaden and accelerate 'pharmacometabolomics-informed pharmacogenomic' studies by eliminating the need for initial genotyping and by making broader SNP association testing possible. METHODS: We previously genotyped 131 tag SNPs for six genes encoding enzymes in the glycine synthesis and degradation pathway using DNA from 529 depressed patients treated with citalopram/escitalopram to pursue a glycine metabolomics 'signal' associated with selective serotonine reuptake inhibitor response. We identified a significant SNP in the glycine dehydrogenase gene. Subsequently, GWAS SNP data were generated for the same patients. In this study, we compared SNP imputation within 200 kb of these same six genes with the results of the previous tag SNP strategy as a rapid strategy for merging pharmacometabolomic and pharmacogenomic data. RESULTS: Imputed genotype data provided greater coverage and higher resolution than did tag SNP genotyping, with a higher average genotype concordance between genotyped and imputed SNP data for '1000 Genomes' (96.4%) than HapMap 2 (93.2%) imputation. Many low P-value SNPs with novel locations within genes were observed for imputed compared with tag SNPs, thus altering the focus for subsequent functional genomic studies. CONCLUSION: These results indicate that the use of GWAS data to impute SNPs for genes in pathways identified by other 'omics' approaches makes it possible to rapidly and cost efficiently identify SNP markers to 'broaden' and accelerate pharmacogenomic studies.

Alcohol craving as a predictor of relapse.

BACKGROUND AND OBJECTIVES: Alcoholism treatment interventions, both psychosocial and pharmacologic, aim to reduce cravings to drink. Yet, the role of craving in treatment outcomes remains unclear. This study evaluated craving intensity measured with the Penn Alcohol Craving Scale (PACS) at admission and discharge from residential treatment as a predictive factor of relapse after treatment. METHODS: The study cohort included 314 alcohol-dependent subjects. Associations between relapse after discharge, PACS score, and clinical variables were investigated using time-to-event analyses. The primary analysis, based on the intent-to-treat principle, presumed relapse in those declining follow-up or not responding to contact attempts. Secondary analysis utilized data from 226 subjects successfully contacted after discharge with a median follow-up time of 365 days. RESULTS: The intent-to-treat analysis demonstrated that relapse was associated with higher level of craving at admission (p= .002) and discharge (p < .001). The analysis of data from patients successfully contacted after discharge led to similar results. A multivariable analysis indicated that relapse rates increased as PACS scores increased, and a higher discharge PACS score was significantly associated with relapse (p= .006) even after adjusting for covariates. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: This study demonstrates that higher PACS scores at the time of admission and discharge are associated with relapse following residential addiction treatment. These data support the role of craving in relapse and the utility of craving measurement as a clinical guide in assessing relapse risk.

Genetic variability in the NMDA-dependent AMPA trafficking cascade is associated with alcohol dependence.

Model studies in mice indicate that the severity of alcohol withdrawal is associated with polymorphic variation and expression of the MPDZ gene. Current knowledge about variation in the human MPDZ gene is limited; however, our data indicate its potential association with alcohol dependence. The multi-PDZ protein is an important part of the N-methyl-D-aspartate (NMDA)-dependent α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor trafficking cascade that controls glutamate-related excitatory neurotransmission. To investigate association of variation in the NMDA-dependent AMPA trafficking cascade with alcohol dependence, we performed a gene-set (pathway) analysis using single nucleotide polymorphism (SNP) data from the Study of Addiction: Genetic and Environment. Rather than testing for association with each SNP individually, which typically has low power to detect small effects of multiple SNPs, gene-set analysis applies a single statistical test to evaluate whether variation in a set of genes is associated with the phenotype of interest. Gene-set analysis of 988 SNPs in 13 genes in the pathway demonstrated a significant association with alcohol dependence, with P < 0.01 for the global effect of variation in this pathway. The statistically significant association of alcohol dependence with genetic variation in the NMDA-dependent AMPA receptor trafficking cascade indicates a need for further investigation of the role of this pathway in alcohol dependence.

Relationship between FKBP5 polymorphisms and depression symptoms among kidney transplant recipients.

BACKGROUND: Several polymorphisms in FK506 Binding Protein gene (FKBP5) and a history of child abuse have been shown to be associated with an increased risk for posttraumatic stress disorder (PTSD). It has also been demonstrated that the same polymorphisms of FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. However, there are only limited numbers of studies replicating the polymorphisms as vulnerability factors for the development of mental illnesses, such as PTSD and depression after stressful life event, especially with a specific incidence, such as kidney transplant surgery. METHODS: A retrospective analysis was conducted using the electronic medical records of 131 adult kidney transplant recipients. Depression severity after kidney transplantation was measured by PHQ-9, and stored blood was genotyped for variants in the Serotonin Transporter (SLC6A4), Brain-Derived Neurotrophic Factor, Catecholamine-O-Methyltransferase, Corticotropin-Releasing Hormone Receptor, and FKBP5 genes. Spearman correlations were used to test for association between genetic variants and depression severity. RESULTS: The rare alleles at three out of four SNPs in FKBP5 (rs1360780, rs9296158, and rs9470080) were associated with increased PHQ-9 scores (P<.05), whereas the last FKBP5 SNP (rs3800373) showed a trend of association (P<.10). All four FKBP5 SNPs are in strong linkage disequilibrium. Although in a subgroup of Caucasian non-Hispanic subjects the association was not statistically significant, the direction of association was consistent with that observed in the entire sample as well as in previous studies. Polymorphisms in genes other than FKBP5 were not associated with PHQ-9 scores. CONCLUSIONS: Polymorphisms in FKBP5 may be associated with higher depression scores in kidney transplant recipients.